Initial ribociclib plus endocrine therapy for HR+/HER2− advanced breast cancer in pre‐ and postmenopausal Chinese women: Primary results from a phase 2 randomized study


 The MONALEESA‐7 and ‐2 phase 3 randomized trials demonstrated a statistically significant progression‐free survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre‐ and postmenopausal patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre‐ and postmenopausal patients with HR+/HER2– ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA‐7 and ‐2 studies.
 Patients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigator‐assessed PFS.
 As of April 25, 2022, the median follow‐up was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies.
 These data demonstrate a favorable benefit–risk profile for ribociclib + ET in Chinese patients.



| Study design and patients
This phase 2, randomized double-blind, placebocontrolled study (Clini calTr ials.gov ID, NCT03671330) evaluated ribociclib + ET in women with HR+/HER2− ABC.Three cohorts of patients were enrolled in mainland China study sites: pharmacokinetics, premenopausal, and postmenopausal cohorts.Results from the pre-and postmenopausal cohorts are reported here.
Eligible patients ≥18 years old had locoregionally recurrent or metastatic HR+/HER2− breast cancer (based on most recently analyzed biopsy).Patients must have had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1 and adequate bone marrow and organ function.Patients must have had either measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or ≥1 predominantly lytic bone lesion; the latter were eligible if disease progression was seen following irradiation of this lesion.
Patients must have been eligible for ET and not received prior hormonal therapy for ABC.Patients who received ≤ 14 days of letrozole or anastrozole (± goserelin) or ≤ 28 days of goserelin for ABC prior to randomization were eligible but must have continued the secondary efficacy endpoints, although OS data were not mature.The safety profile in this population was consistent with that in global studies.

Conclusions:
These data demonstrate a favorable benefit-risk profile for ribociclib + ET in Chinese patients.
same hormonal agent plus goserelin, if premenopausal, during the study.Patients could have had ABC that was either newly diagnosed, treatment naive with progression > 12 months following anastrozole-or letrozolebased therapy, or previously treated with (neo)adjuvant therapy, provided therapy was stopped ≥ 5 half-lives or 7 days, whichever was longer, before randomization.If letrozole, anastrozole, or exemestane was the last (neo)adjuvant therapy, the last dose must have been ≥ 12 months before randomization; for other (neo)adjuvant endocrine agents, no limitations were placed on recurrence timing.
In the premenopausal cohort, patients must have been < 60 years old at the time of informed consent.Premenopausal status was defined by one of the following: a menstrual period in the last 12 months; if on tamoxifen or toremifene in the past 14 days, plasma estradiol ≥ 10 pg/ mL and follicle-stimulating hormone (FSH) ≤ 40 IU/L or in the premenopausal range (local laboratory); or in the case of therapy-induced amenorrhea, plasma estradiol ≥ 10 pg/mL and/or FSH ≤ 40 IU/L or in the premenopausal range (local laboratory).Patients who received ≤ 1 line of chemotherapy for ABC were eligible if treatment was discontinued 28 days before randomization; if the chemotherapy regimen was discontinued for reasons other than disease progression and was given for < 21 days, the regimen was not counted as a prior line.
Postmenopausal status was defined by one of the following: prior bilateral oophorectomy; age ≥ 60 years; age < 60 years with amenorrhea for ≥ 12 months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression); and FSH and estradiol in the postmenopausal range (local normal range).For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol were needed to ensure postmenopausal status.
Patients were ineligible if they had inflammatory breast cancer, prior therapy with a CDK4/6 inhibitor, symptomatic visceral disease, disease burden rendering them ineligible for ET at the investigator's discretion, or central nervous system metastases.Patients with clinically relevant, uncontrolled heart disease and/or cardiac repolarization abnormalities were also ineligible.

| Randomization and blinding
A double-blind, placebo-controlled design was used in both the pre-and postmenopausal cohorts, with patients randomized 1:1 to each treatment arm.Randomization was stratified by the presence of lung and/or liver metastases (yes vs. no) in both cohorts and additionally by receipt of prior chemotherapy for advanced disease (yes vs. no) in the premenopausal cohort only.The patients, investigators, study team, and those involved in study conduct, including local or sponsor-designated radiologists, remained blinded to the treatment identity from randomization until database lock.An independent, unblinded team from the sponsor, not involved in the study conduct or study drug development program, performed 2 interim analyses of the premenopausal cohort, which did not change the study's blinding mechanism, for the sole purpose of sharing results with the health authority.Unblinding of the treatment assignment could occur in the case of medical emergencies, for regulatory reporting purposes, and at conclusion of study.Unblinding for safety was communicated only to an independent statistical group external to the sponsor for reporting to the data monitoring committee (DMC).

| Study treatment, assessments, and conduct
During each 28-day cycle, patients in the premenopausal cohort received letrozole 2.5 mg or anastrozole 1 mg (orally, once daily) plus goserelin 3.6 mg (as a subcutaneous implant on day 1) as well as ribociclib 600 mg (experimental arm; orally, once daily on days 1-21) or matched placebo (comparator arm).Patients in the postmenopausal cohort received letrozole with either ribociclib or matched placebo using the same dosing regimens based on a 28-day cycle.Dose modifications of letrozole, anastrozole, or goserelin were not permitted, but dose reductions of ribociclib/placebo were permitted for tolerability per the investigator's judgment (2 dose reductions maximum, from 600 to 400 to 200 mg/day).Ribociclib dose could not be re-escalated once decreased.
Patients were treated until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination.For patients who discontinued treatment for reasons other than disease progression (including initiation of another antineoplastic therapy), tumor assessments were performed every 8 weeks for 18 months, followed by every 12 weeks until 36 months, and thereafter as clinically indicated until disease progression, death, withdrawal of consent, loss to follow-up, or patient/guardian decision.Patients who discontinued treatment were followed up for safety for ≥ 30 days unless they died, became lost to follow-up, or withdrew consent.All patients were followed up for survival at least every 12 weeks unless consent was withdrawn.The study was considered completed when all patients had discontinued from the study, died, or became eligible to transfer to another clinical study that provided ribociclib to the patient population, whichever occurred first.
Adverse events (AEs) were recorded per Common Terminology Criteria for Adverse Events version 4.03.Additional safety assessments, including physical examination, ECOG PS, echocardiogram, and laboratory tests, were also performed.The DMC reviewed safety data approximately every 6 months in an unblinded manner.
A steering committee that included study investigators and study team members from the sponsor provided study oversight.They were consulted regarding protocol amendments and provided recommendations on publication of study results.The steering committee did not have access to unblinded trial data but did review DMC recommendations and communicated responses to other investigators.
Permitted changes to study conduct due to the COVID-19 pandemic included the possibility for additional study drug to be sent home when considered safe or special arrangements for study treatment via courier or mail service.Onsite monitoring visits were replaced with remote visits, and monitors were directed to consider aspects of site trial management susceptible to the pandemic challenges.The investigators could use local assessments or laboratories when appropriate.

| Study endpoints
The primary endpoint in both the pre-and postmenopausal cohorts was PFS, locally assessed according to RECIST 1.1, defined as the time from randomization to the first documented progression or death due to any cause.PFS was also assessed in subgroups defined by demographic and clinical characteristics to evaluate the consistency of the study results.
Secondary endpoints in the pre-and postmenopausal cohorts were OS, locally assessed RECIST 1.1 overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DOR), and time to deterioration of ECOG PS.Safety and tolerability were also secondary objectives.

| Statistical analysis
The study pursued an estimation strategy for each cohort rather than formal hypothesis testing to demonstrate the consistency of PFS with ribociclib + ET versus placebo + ET in Chinese populations compared with populations in previous global studies (MONALEESA-7 for the premenopausal cohort and MONALEESA-2 for the postmenopausal cohort).In each of the pre-and postmenopausal cohorts, 150 patients were planned to be randomized in a 1:1 ratio to observe 100 PFS events at the time of primary analysis, approximately 23 months after the first patient was randomized.A total of 3 interim analyses were performed, and only the primary analysis of PFS is included in this report.
Efficacy analyses were evaluated in the full analysis set (ITT population) in each respective cohort, which comprised all randomized patients assigned to study treatment.The safety population included all patients who received ≥ 1 dose of any component of study treatment.
The Kaplan-Meier method was used for estimation of the PFS distribution.A Cox regression model stratified by the randomization stratification factors was used to estimate the PFS HR and 95% CI.Patients whose disease had not progressed or were not known to have died were censored at the time of the last adequate tumor assessment prior to the cutoff.If a PFS event was documented after ≥ 2 missing or inadequate tumor assessments, censoring was done at the date of the last adequate tumor assessment.If a PFS event was observed after a single missing or inadequate tumor assessment, the actual date of the PFS event was used.For analysis of response, ORR was presented with Wald 95% CIs.TTR and DOR were also estimated using Kaplan-Meier methods.For OS, the number of events in each arm was reported.For PFS and OS, follow-up was defined from randomization to the date of event or censoring (as described above for the PFS analysis) plus 1 day, expressed in months.
Safety summaries included AEs occurring on or after the first date of study treatment through ≤ 30 days after the date of last study treatment administration.SAS 9.4 software was used to perform data analyses and generate tables and listings.

| Patients
The study was initiated on August 29, 2018, the time of the first patient's first visit.The primary analysis data cutoff was April 25, 2022.Median follow-up from randomization to data cutoff was 34.7 months (range, 31.0-43.5).Patients were enrolled across 25 study sites in mainland China (Table S1): 79 and 77 patients in the ribociclib and placebo arms of the premenopausal cohort, respectively, and 77 in each arm of the postmenopausal cohort.Baseline characteristics were generally balanced between arms in each cohort (Table 1), with a few exceptions in the postmenopausal cohort (e.g., the placebo arm had higher percentages of stage IV disease at initial diagnosis and de novo metastatic disease and had a shorter median duration since initial primary diagnosis).
In the premenopausal cohort, median age across treatment arms was 45.0 years (range, 22-59), with 75.0% of the premenopausal cohort, the most recent therapy was hormonal therapy in 35.3% of patients and chemotherapy in 27.6%; in the postmenopausal cohort, these classes of therapy were given in 24.7% and 25.3%, respectively.At data cutoff, 27 (34.2%)and 35 (45.5%) patients in the ribociclib arms versus 14 (18.2%) and 11 (14.3%) in the placebo arms of the pre-and postmenopausal cohorts, respectively, remained on treatment (Figure 1).In all arms, most treatment discontinuations (66.7%-84.6%)were due to progressive disease.

| Safety
All patients received ≥ 1 dose of study treatment.In the premenopausal cohort, the median duration of exposure to any component of study treatment was 18.5 months in the ribociclib arm and 13.8 months in the placebo arm; in the postmenopausal cohort, the median duration of exposure was 24.9 and 15.6 months, respectively (Table S2).In general, AEs were the predominant reason for dose reductions, interruptions, and delays (Table S3).Dose reductions due to AEs were more frequent in the ribociclib versus placebo arm (premenopausal, 39.2% vs. 2.6%; postmenopausal, 41.6% vs. 6.5%), with most patients requiring only 1 dose reduction (premenopausal, 32.9% vs. 3.9%; postmenopausal, 29.9% vs. 7.8%).Frequencies of dose interruption due to AEs were 74.7% with ribociclib versus 19.5% with placebo in the premenopausal cohort and 75.3% versus 18.2%, respectively, in the postmenopausal cohort.All patients in the ribociclib arms and 96.1% in the placebo arms experienced an AE due to any cause (Tables 3   and S4).No on-treatment deaths were reported in the premenopausal cohort, and 1 per arm (1.3%) was reported in the postmenopausal cohort.The most common all-grade AEs in the ribociclib versus placebo arms, respectively, were neutropenia (premenopausal, 98.7% vs. 29.9%;postmenopausal, 96.1% vs. 20.8%)and leukopenia (premenopausal, 98.7% vs. 46.8%;postmenopausal, 94.8% vs. 32.5%).In the premenopausal cohort, AEs leading to treatment discontinuation occurred in 5 patients each in the ribociclib versus placebo arms (6.3% vs. 6.5%), the most common being prolonged electrocardiogram (ECG) QT (in 2 vs. 1 patients).In the postmenopausal cohort, AEs leading to treatment discontinuation occurred in 11 patients (14.3%) versus 5 (6.5%), the most common being increased aspartate aminotransferase (AST; in 6 vs. 2 patients) and increased alanine aminotransferase (ALT; in 3 vs. 1 patients).All other AEs leading to discontinuation were low frequency (n = 1 each).
AEs of special interest (AESIs; Table S5) were mostly hematologic, as described above.The most common Calculations are based on patients with measurable disease at baseline.b ORR was defined as the proportion of patients who achieved a confirmed CR or PR.
c CBR was defined as the proportion of patients who achieved a confirmed CR, PR, or SD (non-CR/non-PD for ≥ 24 weeks). d Based on patients with a response.e The Brookmeyer-Crowley method was used to calculate 95% CIs for median.nonhematologic AESIs (≥ 25% in any arm) were hepatobiliary toxicity (premenopausal, 59.5% in the ribociclib arm versus 59.7% in the placebo arm; postmenopausal, 58.4% in both arms), QT interval prolongation (premenopausal, 49.4% vs. 6.5%;postmenopausal, 27.3% vs. 5.2%), and infections (premenopausal, 26.6% vs. 10.4%;postmenopausal, 35.1% vs. 31.2%).Hepatobiliary toxicity AESIs predominantly included increased AST and ALT (Table 3).Events requiring dose adjustment and/or interruption were reported in 9 patients per arm (11.4% with ribociclib  vs. 11.7% with placebo) in the premenopausal cohort and 22 (28.6%)versus 9 (11.7%) in the postmenopausal cohort.In the premenopausal cohort, 0% of patients in the ribociclib arm versus 2.6% in the placebo arm discontinued study treatment due to hepatobiliary toxicity AESIs, which in the postmenopausal cohort occurred in 9.1% versus 3.9%.Notable ECG changes from baseline are reported in Table S6.In the premenopausal cohort, a postbaseline Fredericia-corrected QT interval (QTcF) > 480 ms occurred in 16.7% of patients in the ribociclib arm versus 2.7% in the placebo arm.Among these patients, 7.7% in the ribociclib arm versus 2.7% in the placebo arm experienced a postbaseline QTcF interval > 500 ms.An increase from baseline of > 60 ms in the QTcF interval was observed in 19.2% of patients in the ribociclib arm versus 2.7% in the placebo arm.In the postmenopausal cohort, postbaseline QTcF > 480 ms occurred in 10.5% of patients in the ribociclib arm versus 0% in the placebo arm.QTcF events of > 500 ms occurred in 2.6% of patients in the ribociclib arm versus 0% in the placebo arm.An increase from baseline > 60 ms in the QTcF interval occurred in 7.9% of patients in the ribociclib arm versus 0% in the placebo arm.
The median time to first occurrence of and duration of grade ≥ 2 neutropenia, grade ≥ 3 ALT/AST elevation, and grade ≥ 2 QT prolongation are reported in Table S8.

| DISCUSSION
This randomized phase 2 study of ribociclib + ET versus placebo + ET met its primary PFS objective in both pre-and postmenopausal cohorts of women with HR+/ HER2− ABC.In the premenopausal cohort, the study resulted in an estimated 33% relative reduction in the risk of progression or death (HR 0.67 [95% CI: 0.45, 1.01]) in favor of the ribociclib arm and a 12.9-month prolongation of median PFS.In the postmenopausal cohort, the study resulted in an estimated 60% relative reduction in the risk of progression or death (HR 0.40 [95% CI: 0.26, 0.62]) favoring the ribociclib arm, with the median PFS not yet reached.PFS results favoring the ribociclib versus placebo arms were largely consistent across subgroups.ORR was higher and median DOR longer in the ribociclib versus placebo arms in both cohorts.AEs in this Chinese population were manageable, and the overall safety profiles of ribociclib were comparable to those from the global studies, with a few specific safety events such as ECG QT prolongation and hepatobiliary toxicity (primarily increased AST/ALT) observed at higher frequencies.
Efficacy results from this study generally corroborated findings from the global pivotal studies, the most analogous of which were MONALEESA-7 and -2, although cross-trial comparisons should be considered with caution due to differences in study design and populations.PFS results from premenopausal patients showed benefit with ribociclib, as seen in MONALEESA-7; PFS HR was 0.67 (95% CI: 0.45, 1.01) in this study (N = 156) versus 0.55 (95% CI: 0.44, 0.69) in the MONALEESA-7 ITT population (N = 672) and 0.40 (95% CI: 0.26, 0.63) in its Asian subgroup (n = 198) 15 (and 0.47 [95% CI: 0.31, 0.71] in an updated analysis [NSAI subpopulation, n = 166]). 17Likewise, PFS in postmenopausal patients was consistent with that in MONALEESA-2, including the substantial improvement in the Asian subgroup; PFS HR was 0.40 (95% CI: 0.26, 0.62) in this study (N = 154) versus 0.56 (95% CI: 0.43, 0.72) in the MONALEESA-2 ITT population (N = 668) and 0.39 (95% CI: 0.17, 0.91) in its Asian subgroup (n = 51). 16he median treatment durations with ribociclib were longer in this study compared with those from the corresponding MONALEESA studies at the time of primary analysis (e.g., in the ribociclib arms: premenopausal, 18.5 months in this study vs. 15.2 months in MONALEESA-7; postmenopausal, 24.9 months in this study vs. 13.0 months in MONALEESA-2). 15,16While dose reductions were more frequent in the ribociclib arm versus placebo arm, they were consistent with data from the MONALEESA studies (41%-43% in this study had ≥ 1 dose reduction vs. 46% in a pooled safety analysis from MONALEESA-2, −3, and -7 18 ), and efficacy did not appear to be impacted.These observations indicate that effective management of dose-dependent toxicity can be achieved without compromising the efficacy benefit of ribociclib.
The most common AEs in this study were hematologic (mostly neutropenia), similar to the global studies. 15,16rade 1/2 neutropenia occurred at somewhat higher frequencies than in MONALEESA-7 and -2, although grade 3/4 frequencies were comparable. 15,16Similarly, the MONARCH plus study of abemaciclib + NSAI in a cohort of predominantly postmenopausal Chinese patients showed increased AE frequency of mostly lower-grade | 13 of 16 SHAO et al.
0][21] PALOMA-4, a study of palbociclib + letrozole in Asian postmenopausal patients, also showed higher neutropenia frequencies (all grade and grade 3/4) compared with the global PALOMA-1-3 studies. 22,23In the current study, the median time to onset of grade ≥2 neutropenia in the ribociclib arm was approximately 2 weeks, with a similar median duration; in contrast, pooled analyses from the MONALEESA studies showed that despite a similar median time to grade ≥ 2 neutropenia, the median duration was approximately 4 weeks, 24 suggesting that the neutropenia AE resolution may be more rapid in these Chinese patients relative to the pooled, global study populations.
Another notable observation was the incidence of prolonged ECG QT, especially in premenopausal patients.For instance, prolonged ECG QT occurred in 49% of ribociclib-arm patients in this study's premenopausal cohort versus approximately 10% of ribociclib-arm patients in MONALEESA-7's ITT population.These AEs primarily presented as low-grade events, with most not requiring treatment.In this study, the median time to grade ≥ 2 QT prolongation in the ribociclib arms was approximately 2 weeks, with a median duration of ≤ 1.6 weeks, while in the pooled MONALEESA analysis, median time to and duration of grade ≥ 2 QT prolongation were both approximately 2 weeks. 24No torsades de pointes, sudden death, or arrhythmia were reported, and all QT prolongation events were completely resolved after dose modification guidance per protocol.
Findings around hepatotoxicity should also be considered, with the predominant hepatobiliary AESIs, increased ALT or AST, seen in 35%-40% of ribociclib-arm patients in this study versus 10%-15% in MONALEESA-7 and -2. 15,16One grade 5 AE occurred in the ribociclib + letrozole arm (hepatic failure in a patient with disease progression in the liver).In the ribociclib arm of the MONALEESA-7 NSAI-treated Asian subgroup, intermediate incidences of all-grade increased ALT or AST (17% each) were also seen, relative to the ITT population. 17imilarly, increased all-grade AST and ALT were observed in postmenopausal Asian patients (from Hong Kong and Singapore) with HR+/HER2− ABC from the phase 1b MONALEESAsia study with ribociclib + ET (increased AST, 26%; increased ALT, 35%, in patients treated with ribociclib 600 mg + letrozole, n = 23). 25Of note, increased ALT/AST incidences were similar between arms in this study but more skewed toward the treatment arms in the aforementioned ribociclib studies.Furthermore, in this study, the appearance of grade ≥ 3 AST/ALT elevations tended to be observed in the first 4-8 weeks overall, with variable median time to onset and median durations of 1-2 weeks.In pooled MONALEESA analyses, median onset of grade 3/4 AST/ALT elevations was 92 days in the ribociclib + ET arms, with a median duration of approximately 3 weeks. 26These data suggest quicker resolution in the Chinese population compared with global populations (1-2 vs. 3 weeks), similar to neutropenia.
The increased ALT/AST AE frequencies seen in this study's experimental arm were generally similar to those reported in MONARCH plus 19 and PALOMA-4, 23 although the balance of all-grade events between arms differed in each study (with generally similar rates between arms in PALOMA-4, as seen in this study).8][29] Collectively, these data suggest that evaluation of liver function data between Asian and global trials is complex, likely involving the influence of other confounding factors.
Evaluation of therapeutic agents in their target populations is important since ethnic and regional contributions can limit extrapolation of data from one population to another.Overall, this study's patient population represented the intended population from China, although higher disease burden and other associated risk factors were present compared with patients from MONALEESA-7 and -2.For instance, 40%-45% had baseline ECOG PS 1, and approximately 50% had ≥3 metastatic sites, compared with approximately 25% and 35%, respectively, in MONALEESA-7 and approximately 40% and 35% in MONALEESA-2. 15,16espite these population differences, the overall study results are generally consistent with those of the Asian subgroup analyses from the global studies, 15,16 although specific toxicities, mainly low-grade events, were seen at numerically higher rates than in prior ribociclib studies.This observation suggests the influence of intrinsic and/or extrinsic factors affecting AE rates in this population.Still, these data are encouraging given the unique epidemiology of patients with breast cancer in China (e.g., relatively young age, 2 aggressive disease 30 ) and the need for clinically meaningful treatment options in both the pre-and postmenopausal settings.
The study had several limitations.It was not powered to show statistical significance, although it was adequately sized to demonstrate the consistency of results in the Chinese populations compared with populations in prior global studies.The study was also conducted during the global COVID-19 pandemic, and conduct was modified based on this.However, the modifications implemented were related to operational aspects, with minimal impact on the overall integrity or outcome of the study.
In conclusion, this China-based phase 2 study of ribociclib + ET in women with HR+/HER2− metastatic breast cancer met its primary PFS objective in the preand postmenopausal cohorts.The overall safety profile of ribociclib was generally manageable, with no new safety signals observed in either cohort compared with the MONALEESA studies.Collectively, these results complement those reported in Asian patients from global pivotal studies, providing clinical evidence for the use of ribociclib + ET in Chinese patients with HR+/HER2− ABC, supporting approvals for this indication in China.

3. 3 |
Key secondary efficacy endpoints OS data were not mature at the time of analysis (median [range] OS follow-up, 31.7 months [0.4-42.6] in the premenopausal cohort and 32.0 months [1.1-42.3] in the F I G U R E 1 Patient flow diagram.Study cohorts, disposition, and analysis populations are shown.ITT population refers to the full analysis set.G, goserelin; NSAI, nonsteroidal aromatase inhibitor.a The pre-and postmenopausal cohorts are reported here.
Baseline characteristics.The most recent treatment setting for the premenopausal cohort was (neo)adjuvant in 41.7% of patients and metastatic in 21.8%; in the postmenopausal cohort, 49.4% were last treated in the (neo)adjuvant setting.In category includes patients without initial recurrence or progression or with initial recurrence or progression within 90 days of diagnosis with no prior antineoplastic medication.For non-de novo disease category, DFI refers to the time from initial diagnosis to initial recurrence or progression.e Data on prior treatment excludes the short period of prior hormonal therapy (NSAI, with or without G) for advanced breast cancer that was permitted by the protocol.
T A B L E 1 common sites of metastases, present in 66.7%, 63.5%, and 57.1% of premenopausal patients, respectively.In the postmenopausal cohort, the median age was 60 years (range, 36-80), with 71.4% of patients < 65 years of age.In this cohort, 98.7% of patients in the ribociclib arm and 97.4% in the placebo arm had baseline stage IV disease.Most Abbreviations: DFI, disease-free interval; ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; ET, endocrine therapy; G, goserelin; HER2, human epidermal growth factor receptor 2; LET, letrozole; NSAI, nonsteroidal aromatase inhibitor; PBO, placebo; PR, progesterone receptor; RIB, ribociclib.a All patients in the premenopausal cohort had stage IV disease at study entry; in the postmenopausal cohort, 1 patient (1.3%) in the RIB arm and 2 (2.6%) in the PBO arm had stage III disease at study entry.b One patient (1.3%) in the PBO arm of the postmenopausal cohort had pancreas metastases.One patient in the PBO arm of the postmenopausal cohort had metastatic site information that was not available.c Other refers to any metastatic site other than soft tissue, bone, lung, liver, skin, or lymph node.d De novo disease Secondary efficacy endpoints a .
T A B L E 2Note: The 95% CIs for each variable represent exact binomial confidence intervals.Abbreviations: CBR, clinical benefit rate; CR, complete response; G, goserelin; LET, letrozole; NR, not reached; NSAI, nonsteroidal aromatase inhibitor; ORR, overall response rate; PBO, placebo; PD, progressive disease; PR, partial response; RIB, ribociclib; SD, stable disease.a Most common AEs regardless of attribution.
T A B L E 3 Only one grade 5 AE was seen in the ribociclib + letrozole arm, hepatic failure, in a patient who had disease progression in the liver.b All-grade events occurring in ≥ 25% and grade ≥ 3 AEs occurring in > 5% of patients in any arm. a